Obesity is a chronic, complex, multi-factorial disease, involving social, cultural, genetic, physiological and psychological components, and is associated with substantially increased morbidity and mortality. Over-nutrition is attributed as the cause of about 400,000 deaths a year in the USA (Mokdad, 2004), and may considered to be an epidemic. Based on the body-mass index, defined as the ratio of weight and squared height, (ranging normally from 18.5 to 24.9), about one third of the adult population is overweight (an index of from 25 to 29.9), and more than one quarter is obese (index greater than 30) (National Center for Health Statistics, 2000). Environmental and behavioral changes brought about by economic development and modernization have been linked to the rise in global obesity. The environmental factors which foster the tendency toward obesity include lack of physical activity combined with high-calorie foods. The prevalence of overweight and obesity is increasing worldwide at an alarming rate in both developing and developed countries, in children and adults, men and women. The number of overweight and obese people has continued to increase since 1960, a trend that is not slowing down. Today, 64.5% of adult Americans—about 127 million—are categorized as being overweight or obese and nearly one-third (30.5%)—about 60 million—are obese, as reported in the National Health and Nutrition Examination Survey (NHANES) by the Centers for Disease Control and Prevention (CDC).
Obesity significantly increases the risk of illness from about thirty serious medical conditions and is associated with increases in deaths from all-causes. Among these are high blood pressure, diabetes, osteoarthritis, heart disease, stroke, gallbladder disease and cancer of the breast, prostate and colon (National Task Force on the Prevention and Treatment of Obesity, 2000). Furthermore, each year, obesity causes at least 300,000 excess deaths in the U.S., being the second leading cause of unnecessary deaths. Healthcare costs of American adults with obesity amount to approximately 100 billion dollars.
Weight gain has also been found to occur as a result of various factors, including, for example, use of certain drugs, cessation of smoking, and advent of a holiday season.
Drugs which are known to cause weight gain include antipsychotics, particularly atypical antipsychotics; antidepressants, particularly the tricyclic antidepressants; mood-stabilizers; calcium channel blockers; anti-convulsants; proton pump inhibitors; antidiabetic agents; antihypertensives; and hormones. Certain selective serotonin-reuptake inhibitors (SSRIs) also have an effect on weight gain, although other SSRIs, such as, sertraline, sibutramine and fluoxetine, often have the opposite effect, and are, in fact, used as appetite suppressants.
Weight gain associated with use of certain drugs may significantly affect patient compliance with the drug administration regime.
Certain drug categories, such as the SSRIs and tricyclic antidepressants, cause—food cravings,—. Furthermore, such drugs may stimulate appetite by blocking of histamine receptors. For example, it has recently been shown that atypical antipsychotics, such as olanzapine and clozapine, as well as tricyclic and tetracylic antidepressants, such as amitriptyline and mirtazapine, respectively, which are potent H1 antagonists, have a high propensity to induce weight gain (Wirshing 1999).
Atypical antipsychotics have been frequently cited as causing a higher increase in weight gain than conventional antipsychotics (see, for example, Bustilllo, 1996). Weight gain was found to be greatest with clozapine, olanzapine, risperidone, and quetiapine, and less with aripiprazole and ziprasidone, and an additive effect on weight gain was found to occur in patients treated with antipsychotic medications and concomitantly with a drug from another class which may cause weight gain through a different mechanism, such as valproate (Kane, 2003). Weight gain with clozapine and olanzapine was found to persist for up to 30 weeks of treatment, and to be associated with a higher mean weight gain than for risperidone, haloperidol and sertindole (Wirshing, 2004). Risperidone-treated patients were found to gain weight for an initial 8-week period and then reach plateau level. Weight gain was also found to be more problematic for children and adolescents than for adults.
The mechanisms by which antipsychotic drugs cause weight gain are not clear. Antipsychotic drugs have multiple effects on neurotransmitter systems, which in turn have a range of effects on energy homeostasis. Most of the antipsychotics work through some degree of dopamine blockade (Wirshing, 2004), but modulation of the serotogenic, histaminergic, and adrenergic systems, all of which have potential impact on weight regulation, may also be involved. Most of the atypical antipsychotics work through a combination of receptor systems. Olanzapine and clozapine have the highest affinity for the H1 receptor of all the atypical antipsychotics, and are also associated with the highest weight gain. A logarithmic relationship between H1 receptor affinity and weight gain has been demonstrated (Wirshing, 1999). In addition, many atypical antipsychotics exhibit activity at several serotonin receptor subtypes, including the 5-HT2C subtype, which appears to mediate some effects on appetite. Olanzapine and clozapine both have high affinities for 5-HT2A, 5-HT2C, H1-histaminergic, and M1-muscarinic receptors. Clozapine also has high affinity for α1-adrenergic receptors. Ziprasidone, which is associated with minimal weight gain, has more serotogenic and less adrenergic, histaminic and muscarinic receptor affinity. Quetiapine has relatively high affinity for histamine receptors; risperidone has modest H1 affinity, but notable affinity for 5-HT2A and 5-HT2C receptors. There are also endocrine effects of atypical antipsychotics, which presumably also play a role in weight gain.
A dual effect of the atypical antipsychotics in weight gain has been proposed: one, appetite stimulation by a direct effect on the brain, that may be observable in the short term; and second, a delayed endocrine/metabolic dysfunction that promotes fat deposition (Baptista, 2004). Involvement of the cytokine peptides leptin and tumor necrosis factor (TNF)-α in anti-psychotic-induced weight gain has also been suggested.
The use of atypical antipsychotics has also been found to place patients at risk for various metabolic disorders, including metabolic syndrome, which results in weight gain, as well as in hypertriglyceridemia, and in increased insulin, glucose, and low-density lipoprotein cholesterol levels (Lieberman, 2004). According to a recent review (Newcomer, 2005), clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidemia. A smaller effect is observed with risperidone and quetiapine. In general, it appears from the rank order of risk of diabetes and dyslipidemia observed for the atypical antipsychotics, that the risk is related to the differing weight gain liabilities of the drugs. It is suggested that the increased incidence of diabetes in patients receiving antipsychotics is not due purely to weight gain, since patients can develop diabetes without significant weight gain, and diabetes usually improves rapidly when the antipsychotic is withdrawn (Koller, 2001; Koller, 2002). The mechanisms leading to diabetes can include the drug induced weight gain, but there is also evidence of a direct metabolic effect. This may be related to antagonism at the 5-HT2 or histamine H1 receptors or to an elevation of serum leptin beyond that induced by increased body weight alone (Lean, 2003).
Dyslipidemia is most often associated with clozapine and olanzapine, and is primarily seen as an increase in triglyceride levels, but may also manifest as increased total cholesterol, LDL-cholesterol and decreased HDL-cholesterol (Barrett, 2004).
The use of atypical antipsychotics have also been associated with an increase in eating disorders, such as binge eating disorder, and bulimia nervosa (Theisen, 2003), which may be a secondary effect of the weight gain associated with these medicaments, resulting in reduced self esteem and repeated unsuccessful dietary trials.
Weight gain commonly occurs also as a result of cessation of smoking. This may be due to the fact that smoking burns calories, artificially elevates heart rate and increases metabolism. Upon cessation of smoking, the subject has to readjust to a lower metabolic rate.
Furthermore, nicotine is an appetite suppressant. Nicotine stimulates release of adrenaline, which acts upon the liver to step-up the breakdown of glycogen so that more glucose will be liberated into the blood. Nicotine also affects release of insulin, which controls glucose levels in the blood. Hence, nicotine causes slight hyperglycemia, and as a result, the body and brain may slow down the hormones and other signals that trigger feelings of hunger.
In addition, a subject suffering from nicotine withdrawal may turn to food for emotional comfort. Also, since smoking dulls the taste buds, food begins to taste better to new non-smokers, which can lead to increased food intake. Weight gain may also be caused by drugs prescribed to assist in smoking cessation. Anti-smoking medications include Zyban™ (bupropion hydrochloride).
Weight gain frequently also occurs during a holiday season, when the subject may have more opportunity to over-indulge in food, due to increased leisure time, increased availability of food, reduced exercise etc., or due to increased participation in meals in a social context. Such weight gain is greater during holidays, such as religious or national holidays, which are associated with consumption of specific foods or festive meals. Examples of such holidays include Thanksgiving, Christmas, and Passover.
There are several different treatment options for management of weight, including: dietary therapy, physical activity, behavior therapy, drug therapy and surgery. For the majority of overweight and obese people, who find they are unable to change their lifestyle, drug therapy is the most favorable and applicable option. Although hundreds of millions of people are seeking drug therapy for the treatment of obesity, current drug therapies do not meet this need due to their undesired side effects and limited efficacy.
Medications for the treatment of obesity are currently approved for use in adults with a body-mass index of 30 or higher, or with a body-mass index of 27 or higher who have obesity-related medical problems (Physicians' Desk Reference, 2001). Approximately 10 percent of women and 3 percent of men with a body-mass index of 30 or higher reportedly use weight-loss medications (Serdula, 1999).
Medications currently approved for weight loss in the United States fall into two categories: those that decrease food intake by reducing appetite or increasing satiety (appetite suppressants), and those that decrease nutrient absorption. A potentially third category, medications increasing energy expenditure, such as ephedrine, is not currently approved for treating obesity in the United States.
The only FDA-approved medication for obesity that reduces nutrient absorption is orlistat (Xenical™), which acts by binding to gastrointestinal lipases in the lumen of the gut, preventing hydrolysis of dietary fat into absorbable free fatty acids and monoacylglycerols.
Most appetite suppressants work primarily by increasing the availability of anorexigenic neurotransmitters—notably norepinephrine, serotonin, dopamine, or some combination of these neurotransmitters—in the central nervous system. Noradrenergic drugs available in the United States include phentermine, diethylpropion, phendimetrazine, and benzphetamine. Some of these drugs are considered by the Drug Enforcement Administration (DEA) to have a potential for abuse. Amphetamines, which are considered to have a particularly high potential for abuse are no longer recommended for weight loss for this reason. The Food and Drug Administration (FDA) approves the medications for use of “a few weeks” only (generally presumed to be 12 weeks or less) for the treatment of obesity.
Side effects of noradrenergic medications include insomnia, dry mouth, constipation, euphoria, palpitations, and hypertension (Physicians' Desk Reference, 2001).
Serotonergic agents act by increasing the release of serotonin, inhibiting its reuptake, or both. Fenfluramine (Pondimin™) and dexfenfluramine (Redux™), medications that both stimulate serotonin release and inhibit its reuptake, were withdrawn from the market in the United States in 1997 because of associations with valvular heart disease and pulmonary hypertension. Some selective serotonin-reuptake inhibitors have induced weight loss in short-term studies, and fluoxetine (Prozac) has undergone considerable evaluation to determine its efficacy for weight loss (Goldstein, 1993). However, after initial weight loss, steady regain was observed in later stages of the treatment (National Task Force on the Prevention and Treatment of Obesity). Sertraline (Zoloft™), evaluated as an adjunct for weight maintenance after a very-low-calorie diet, showed a similar lack of long-term efficacy (Wadden, 1995). Sibutramine (Meridia™, Reductil™), an inhibitor of both norepinephrine reuptake and serotonin reuptake that also weakly inhibits dopamine reuptake, is approved by the FDA for weight loss and weight maintenance in conjunction with a reduction diet. Side effects of sibutramine include increased blood pressure and pulse frequency rate (McMahon, 2000).
Rimonabant (Sanofi), which is claimed to stop food cravings, represents a new class of drugs that inhibit the activity of the CB1 receptor. The CB1 receptor forms a part of the endocannabinoid system. The CB1 receptor has been found in the brain, fat cells and other parts of the body, and has been associated with regulating food intake and with tobacco dependency (Pi-Sunyer et al., 2004). The endocannabiniod system helps to regulate pleasure, relaxation, and pain tolerance. Little is currently known about the long-term effects of inhibition of this system. Further, neurologists point out that the endocannabinoid system helps to protect the brain under some circumstances (such as stroke and head injury,) such that brain damage in these circumstances might be worse in patients taking drugs that block the endocannabiniod system.
The Rimonabant drug is currently undergoing phase III clinical trials. Presently reported side effects associated therewith include anxiety, nausea and diarrhea.
Hence, although some of the currently approved medications show moderate effects and can help some patients in losing weight, there is a continuing need for efficacious treatment regimes and drugs for alleviating the serious and prevalent disorder—the weight excess.
Histamine, a potent bioactive substance that has been studied for nearly a century, is an aminergic neurotransmitter. Four histamine receptors have been identified: H1, H2, H3, and H4, leading to the discovery and therapeutic use of potent receptor antagonists. Activation of the H1 receptor is associated with effects on smooth muscle and central neurons; activation of the H2 receptor stimulates acid secretion in the stomach, while activation of the H3 receptor results in a pre-synaptic autoregulatory effect.
Histamine has been implicated, among others, in the regulation of arousal state (Lin et al., 1990), locomotor activity (Clapham, 1994), cardiovascular control (Imamura, 1996), water intake (Lecklin, 1998), food intake (Leurs, 1998), and memory formation (Blandina, 1996). It has been suggested that histaminergic neural circuits arising in the tuberomammilary nucleus and projecting into the satiety centers of the hypothalamus participate in regulation of food intake. Histaminergic neurons project into hypothalamic centers known to participate in food intake i.e. the paraventricular nucleus and ventromedial hypothalamus, where the anorectic effect is thought to be mediated by postsynaptic histamine H1 receptors. The density of this receptor, together with the H3-receptor-mediated control of the intrasynaptic concentration of histamine, both seem to be crucial for the strength of the anorectic signal. Some studies have indicated that histamine may suppress appetite by acting on hypothalamic histaminergic neurons that participate in the regulation of food intake (Sakata, 1997; Bjenning, 2000; Sakata, 1995). Thus, it was reported that histamine injected intracerebroventricularly acts as an appetite suppressant, and that depletion of histamine stimulates feeding (Tuomisto, 1994). Changes in histaminergic tone in the CNS have been associated with genetic models of obesity (Machidori, 1992). In addition, intracerebroventricular injection of leptin has been correlated with changes in the turnover rate of hypothalamic neuronal histamine (Yoshimatsu, 1999). Since histamine is unable to cross the blood brain barrier, these effects would not be expected to be seen with systemic administration of histamine.
In both humans and rodents, treatment with an H1 antagonist resulted in hyperphagia (Fukagawa, 1989), and administration of H3 antagonists led to hypophagia (Attoub, 2001). The selective histamine H3 receptor antagonist NNC 38-109 has been reported to increase hypothalamic histamine levels, in parallel with decreases in food intake and body weight, according to studies in intact HEK293 cells expressing human or rat histamine H3 receptors (Malmof, 2005). The intrasynaptic concentration of histamine is primarily controlled by feedback signals from presynaptic histamine H3 receptors that inhibit both the conversion of L-histadine to histamine and the release of histamine into the synaptic clefts. Thus, by reducing the inhibition using a selective histamine H3 receptor antagonist, the synaptic concentration of histamine increases together with the signaling from the histamine H1 receptor, and food intake is consequently inhibited. However, the long-term effects of H3 receptors on anorexigenic activities for body-weight homeostasis have not been documented because of the off-target activity (Leurs, 1995) and toxicity profile of H3 inhibitors (Onderwater, 1998).
Betahistine is an orally active histamine-like drug extensively used in the symptomatic treatment of vestibular disorders, mainly Menier's disease and vertigo (including vertigo in patients with migraine (Amelin, 2003), dizziness with recurrent vertigo (Acta Otolaryngol., 2003), vertigo in patients with vascular and traumatic cerebral injuries (Gusev, 1998), and benign paroxysmal positional vertigo (Fujino, 1994)). Studies have shown that betahistine can be further utilized in the treatment of a variety of disorders, including the after-effects of craniocerebral injury and vascular events (Odinak, 2005), preventing or reducing myocardial infraction after occurrence of coronary occlusion (U.S. Pat. No. 4,159,332), multiple sclerosis (Boika, 2002), cutaneous hypersensitivity in patients with grass pollen allergy (Synman, 1995), arteriosclerotic dementia (Seipel, 1977), acute deafness (Grahne, 1976), vertebral-basilar insufficiency (Botez, 1975), and seasickness (J. Vestib. Res. 2003).
Betahistine is a structural analog of histamine, in which the imidazole ring of the histamine is replaced by a pyridine ring. Betahistine is an H1 receptor agonist, and has been found to exhibit an H1-agonism activity of about 0.07 times that of histamine, and to cause hypotensive response, bronchoconstriction, and increased vasopermeability after parenteral administration. Receptor binding studies have also shown that betahistine is a potent H3-receptor antagonist. Betahistine is able to cross the blood brain barrier and act centrally by enhancing histamine synthesis is tuberomammillary nuclei of the posterior hypothalamus. Adverse side effected associated with betahistine are typically minor and include skin rashes of various types, urticaria, and itching. Gastric upset, nausea, and headache have also been reported by some patients.
It has been found (Rossi et al., 1999) that high doses of betahistine, delivered intraperitoneally, increased water intake and decreased food intake in pygmy goats. This was suggested as being due to stimulation of both H1 and H2 receptors, since in addition to its known action as an H1 receptor agonist, betahistine has been shown to act as a weak partial agonist of peripheral histamine H2 receptors (Arrang et al., 1985). This idea is further supported by recent findings showing that the hypophagic effect of histamine was blocked by the H2-receptor antagonist, cimetidine, in pygmy goats. These similarities in the hypophagic effects of histamine and betahistine suggest an involvement of H2-receptors in the hypophagic effect of betahistine in pygmy goats. H2-receptors are not, however, associated with weight change in humans (Rasmussen, 1993).
Szelag et al. (2001) found that betahistine, when given intraperitoneally, decreased food intake in rats, whereas this effect was not seen when betahistine was given intragastrically (Szelag, 2002). It was suggested that the effect of betahistine administration on food intake involves increasing histamine synthesis and release as a result of H3 receptor inhibition. However, since activation of H2 receptors is known to stimulate hydrochloric acid secretion (see, for example, Clayman, 1977), it was further suggested that the lack of the influence of betahistine on food intake after intragastrical administration may be due to the fact that betahistine increased hydrochloric acid release by activation of H2 receptors, thereby abolishing the central anorectic activity of betahistine.
It was also suggested that the effects on H1 receptors in humans may differ significantly from those in rats due to variations in circadian rhythm between the species. Therefore, it appears that the anorectic response of betahistine is dependent upon species and route of administration. Nevertheless, Szelag et al. fails to teach the effect of betahistine administered orally or by any other route of administration, on food intake in humans.
Lecklin et al. (2002) found that inhibition of histamine catabolism by intraperitoneal injection of metoprine, a histamine-N-methyltransferase inhibitor, resulted in suppressed daily energy intake and ingestion of fat in rats.
Pharmacokinetic studies showed that betahistine is transformed, mainly in the liver, to 2-(2-aminoethyl)-pyridine (AEP) and to 2-(2-hydroxyethyl)-pyridine (HEP), (Sternoson, 1974) whereas both betahistine and the metabolites bind to histamine receptors.
The cited references corroborate the complexity of appetite regulation, which includes, among other factors, species specificity and route of administration. It has further been found (Seifert et al., 2003) that multiple differences exist in agonist and antagonist pharmacology of histamine receptors between different species, such as humans and guinea pigs. The prior art does not teach or suggest the use of H1 agonists for regulating food intake in humans. The prior art further does not teach or suggest the use of such H1 agonists that have a pharmacological half life that permits an efficient treatment therewith. The prior art further does not teach or suggest the use of orally administered H1 agonists for regulating food intake in humans.
There is thus a widely recognized need for and it would be highly advantageous to have histamine-related agents for regulation of food intake in humans and for reducing weight gain associated with e.g., drug treatment, devoid of the above limitations.